Over the last 20 years, many classes of biodegradable polymers have been under development for a wide variety of biomedical applications. (Domb, et al, 1994) The most actively pursued biomaterials include: the lactide/glycolide copolymers, polyorthoesters, polycaprolactones, polyphosphazenes and Polyanhydrides. (Domb, et l, 1994, 1992, 1993) One of the widely studied applications of these polymers is their use in implantable drug delivery systems. For this application, polyanhydrides are a unique class of polymers because some of them demonstrate a near zero order drug release and a relatively rapid biodegradation in vivo.
Some of the desired physico-chemical and mechanical properties in a single polymer that could be used in an implantable or injectable drug delivery system are:
a. hydrophobic enough so that the drug is released in a predictable and controlled way; PA1 b. be biocompatible when implanted in the target organ; PA1 c. being completely eliminated from the implantation site in a predictable time; PA1 d. suitable physical properties for device fabrication properties (low melting point, usually below 100.degree. C. and soluble in common organic solvents); PA1 e. flexible enough before and during degradation so that it does not crumble or fragment during use; and PA1 f. easy to manufacture at a reasonable cost.
Some of these ideal properties are displayed by some of the polyanhydrides. For example, poly(carboxyphenoxy propane) [P(CPP)] displays near zero order erosion and release kinetics. (Leong et al 1985) However, this polymer displays an extremely slow degradation rate, and it is estimated that a drug delivery device prepared from P(CPP) would take almost three years to completely degrade in vivo.
In U.S. Pat. No. 5,171,812, a class of aliphatic copolyanhydrides was synthesized from dimers and trimers of unsaturated fatty acids (FAD and FAT, respectively) with sebacic acid. This class of polymers were demonstrated to have the properties suitable for developing various types implantable drug delivery devices, including: microspheres, films, rods, and beads.
In a recent publication, Domb and Manis, 1993), a class of aliphatic copolyanhydrides was synthesized from nonlinear hydrophobic dimers (FAD) of erucic acid and sebacic acid (SA). This class had some bitcompatible characteristics even though there was a rapid partial degradation within the first ten days with the release of the SA component, a residue which is mostly the FAD comonomer remains and is not easily degraded.
Although these polymers were found suitable for drug delivery applications both in vivo and in vitro, studies in dogs showed that when implanted in muscle, the polymer degraded to the synthetic fatty acid dimer which was not eliminated from the implantation site even after six months. This semisynthetic fatty acid dimer is not easily metabolized in the body because it contains a non-natural structure of a C--C bridge (Structure 1) which is difficult to be metabolized by body enzymes. ##STR1##
The FAD and related oligomers of fatty acids are the coupling products of two or more unsaturated fatty acids in which the original fatty acids are connected via a chemically stable C--C bond (non-hydrolyzable). Because the oligomerized fatty acids contain a non-natural structure (C--C branching points), they may not be eliminated at the same rate and capacity as natural fatty acids, which are readily eliminated from the body by a .beta.-oxidation process.